This application is in response to the goals of the Cutting Edge Basic Research Award (CEBRA) program: "Develop or adapt innovative techniques or methods for addiction research." Our objective is to develop an innovative technique to delineate between the formation of cocaine-associated contextual and cued memories in a modified conditioned place preference (CPP) paradigm. The CPP paradigm entails appetitive Pavlovian conditioning and is utilized to investigate several elements of addictive behavior, such as habit formation and reactivity to drug-associated environment, as well as extinction and reinstatement of conditioned behavior. However, a typical CPP design does not allow dissociation between cue- and context-dependent conditioning, both of which have been extensively investigated in aversive Pavlovian fear conditioning but not in appetitive conditioning. Given that context and cues that had been associated with a drug-reinforcer can elicit drug craving and relapse in humans, it is critical to investigate the roles of context and cue conditioning in animal models of addiction. The formation of contextual memory involves spatial hippocampus-dependent learning while the formation of cued memory involves emotional amygdala-dependent learning. Drug-associated contextual and cued memories are thought to play a role in the development of drug addiction. We refer to the context as a discrete place and to the cue as a discrete light that had been paired with drug administration. Our preliminary studies have shown that pairing cocaine administration with a flashing light cue in a discrete context elicits the formation of distinct cued and contextual memories. We hypothesize that this new conditioning paradigm allows delineation between drug-associated contextual and cued memories in the course of the a) acquisition, b) reconsolidation, and c) extinction of such memories. Using wild type (WT) and neuronal nitric oxide synthase (nNOS) knockout mice as well as pharmacological tools, we will investigate how this new conditioning paradigm can be utilized to delineate between cocaine-associated cued and contextual memories. First, the acquisition (Aim 1) and reconsolidation (Aim 2) of cocaine-associated contextual and cued memories will be investigated. Second, the influence of the environment of extinction training on subsequent responses to cocaine-associated contextual and cued stimuli will be investigated (Aim 3). The studies proposed will develop a novel straightforward behavioral paradigm to investigate learning and memory processes relevant to the underlying course of drug addiction. Results of these studies could lead to the development of new pharmacotherapies for the treatment of drug addiction. PUBLIC HEALTH RELEVANCE: This proposal focuses on the development of a novel straightforward behavioral paradigm to investigate the formation of drug-associated contextual and cued memories. Understanding the learning and memory processes associated with the development of drug addiction will lead to the development of pharmacotherapies and behavioral interventions for the treatment of drug addiction.